Simple method predicts stereochemistry The stereochemical outcome of many organic reactions now can be pre dicted by means of a simple calcula tion that "anyone can do on a paper napkin," according to Georgia Insti tute of Technology's Edward M. Burgess. He and his colleague, Charles L. Liotta, also of the chem istry department, spent much of their spare time during the past five years developing and simplifying their new predictive model. The roots of the new method reach back further in time to principles es tablished by the Japanese chemist Kenichi Fukui of Kyoto University. He convinced organic chemists that a reaction's outcome can be predicted successfully by analyzing what takes place in "the frontier orbitals," from which electrons are most easily lost or into which they're most easily in serted. His methods, developed over about the past 25 years, permit one to predict at which atoms a reaction is most likely to occur. However, Fukui's approach "does not adequately generalize about the stereochemistry" of reactions, Liotta says, and thus leaves unexplained certain peculiarities within the or ganic literature. For instance, there is a set of nucleophilic reactions in which the attacking molecule ap proaches the reaction site on the same side of the molecule from which an other molecular fragment is leaving. Hand-waving invocations of steric hindrance won't explain such phe nomena, but the new rules devised by Burgess and Liotta can. One major simplifying principle that helped the Georgia Tech chem ists was limiting analysis "just to the fragment where the reaction is taking place," Burgess says. "That's the se cret; you don't have to calculate the whole thing." Instead, they've con cocted a small set of "staple" ingre dients to watch and whose behavior typifies—and thus is predictive for—most other organic fragments. This small set of molecular frag ments, whose important molecular orbital properties can be memorized easily, includes a carbon-hydrogen sigma bond; a bond between carbon and elements in the second row of the periodic table, such as carbon, nitro gen, or oxygen; a carbon-carbon double bond; and a carbon-carbon triple bond. "No matter how complicated a molecule is, a calculation with these fragments allows predictions," Liotta
Liotta and Burgess developed technique in their spare time
says. The decision to go ahead with this limited set of fragments was "not intuitively obvious," however. He admits that they were derived from published accounts of "high-grade computer molecular orbital calcula tions." With those fragments in hand, the stereochemical course of an organic reaction is predicted by something called perturbation theory. In simple terms, perturbation theory describes how crucial orbitals where key bond ing electrons reside are distorted and reshaped during the course of a reac tion. Theory about the way orbitals mix is "a little bit gruesome," Burgess admits. It is laid out in hefty, multi ple-term equations that make all but the most dedicated feel squeamish about their computer bills. Fortunately, Burgess and Liotta's method figuratively short-circuits the computer, or at least the need of one. "All we need to know is the sign," Liotta explains, "not the numbers." Thus, the signs for each term, which themselves are based on mo lecular fragments, are plugged into an equation. Then, the sign of the sec ond-order mixing coefficient is de termined, merely by multiplying all of the signs of the terms within the equation. "You don't need a com puter, just a pencil and paper to do this," Burgess says. An important principle in setting up this simplified calculation, he adds, is that "domi nant terms" are derived from "sym metry-allowed interaction of levels closest in energy." Following these rules in the prescribed way shows how π and σ orbitals mix and distort, thus indicating from what direction new bonds form. And that's stereochem istry being predicted, plain and simple. The method also delineates certain differences in comparing one
nucleophilic reagent with another. Those differences depend directly on which electron orbitals are involved in a reaction, making sulfur with its d-like orbitals different from nucleophiles such as nitrogen. "This is not a simple paper to read in 30 minutes," Liotta says of the re cently published account of the new method [J. Org. Chem., 40, 1703 (1981)]. But the gist of the material is being taught as part of a graduate course in physical organic chemistry at Georgia Tech. Students need to have some mastery of frontier orbital theory. But, besides that, under standing these new rules and being able to put them into use ought not to take any more effort than compre hending the Woodward-Hoffmann rules, Burgess contends. The project to develop a predictive model is continuing, according to the Georgia Tech chemists. For example, they would like to make the model applicable to organometallic reac tions. Extending the model in that direction ought to be fairly straight forward. The Georgia Tech chemists say that other theoreticians may chal lenge this model for its simplicity. It is, after all, a qualitative analysis that stops short of being a comprehensive step-by-step calculation. Nonethe less, so far it works ably. The project to derive this predic tive model has been conducted in formally in several respects. Burgess and Liotta never asked for direct grant support to undertake this project. Instead, they squeezed out the work during spare time and be tween projects, although they do ac knowledge indirect support from the National Science Foundation for providing "unencumbered summers" to do some of the research. Jeffrey Fox, Washington May 11, 1981C&EN
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